Cross-Linking of CD80 on CD4+ T Cells Activates a Calcium-Dependent Signaling Pathway

CD80 expressed on the surface of APCs provides a positive costimulatory signal to naive CD4(+) T cells via CD28 during activation. However, CD80 is also expressed on the surface of activated CD4(+) T cells, and cross-linking CD80 on the surface of CD4(+) T cells activated in the presence of Th1-promoting cytokines induces a direct up-regulation of T-bet, IFN-gamma, and Bcl((XL)) expression in primary CD4(+) T cells. The present data show that naive CD4(+) T cells activated in Th1-promoting conditions in the presence of anti-CD80 mAb increase the level of IFN-gamma produced by increasing the rate of IFN-gamma mRNA transcription, which is supported by an increase in the level of T-bet phosphorylation and T-bet binding to the third intronic enhancer in the IFN-gamma locus. Furthermore, anti-CD80 mAb-induced increase in IFN-gamma expression and T-bet phosphorylation is dependent upon the activation of a Ca2(+)-dependent pathway as shown by anti-CD80 mAb-induced intracellular Ca2(+) flux following CD80 cross-linking. These findings indicate a novel regulatory role for CD80-mediated intracellular signals in CD4(+) T cells and have important implications for disease therapies using anti-costimulatory mAbs as use of an intact CD80 mAb may lead to CD80 cross-linking on activated T cells and enhanced proinflammatory cytokine production. The Journal of Immunology, 2009, 182: 766-773.